Device and methods for directing agents to the middle ear and the inner ear

ABSTRACT

This disclosure includes a method for pushing an active agent into a patient&#39;s ear via the device. The agent can be pushed to a treatment site.

PRIOR RELATED APPLICATION DATA

This application claims priority of U.S. Provisional Application Ser.No. 61/603,076, filed Feb. 24, 2012 and is a continuation in part ofU.S. application Ser. No. 13/684,521, filed Nov. 24, 2012, pending,which is a continuation of U.S. application Ser. No. 12/712,182, filedFeb. 24, 2010, now U.S. Pat. No. 8,316,862, which claims priority toU.S. Provisional Patent Application Ser. No. 61/155,223, filed Feb. 25,2009, the entire contents of which are incorporated herein by referencein their entirety.

BACKGROUND

This disclosure relates generally to the delivery of agents to the earof a mammal. More specifically, this disclosure relates to the deliveryof therapeutics agent, pharmaceutical agents, molecular agents,nucleotides, or proteins to the inner or middle ear and their use inallowing such therapeutic agents to be administered into the inner ormiddle ear.

SUMMARY

This disclosure includes a method for treating a patient or animal thatincludes providing a delivery device capable of generating a magneticfield, placing the device proximal to a patient's ear, and pushing anagent into the patient's ear via the device, wherein the therapeuticagent is pushed to a treatment site.

Additional features of the disclosure will become apparent to thoseskilled in the art upon consideration of the following detaileddescription of illustrative embodiments exemplifying the best mode ofcarrying out the disclosure as presently perceived.

BRIEF DESCRIPTION OF THE DRAWINGS

The detailed description particularly refers to the accompanying figuresin which:

FIG. 1 shows one exemplary embodiment is a device 10 formagnetically-assisted delivery of an active agent.

FIG. 2A shows one illustrative example of a magnetic device capable ofdirecting or applying a force on a magnetic or magnetizable agent.

FIG. 2B illustrates one specific method to deliver active agents to themiddle ear.

FIG. 3 illustrate a method to deliver active agents from the middle earto the inner ear.

FIG. 4 shows one illustrative example of a device suitable with certainembodiments.

FIG. 5, one exemplary device can make use of magnetic elements ormagnets that may be capable of generating magnetic fields.

DETAILED DESCRIPTION

Specific embodiments provide methods, devices and systems for directingan active or therapeutic agent to and into the middle and inner ear. Oneexemplary embodiment is a device 10 for magnetically-assisted deliveryof an active agent schematically shown in FIG. 1. One operativeprinciple for magnetically directing (e.g., with force F) the agent (ortherapeutics) associated with magnetic particles (e.g. with Fe₃O₄cores), which includes magnetizable nano-particles, involves anarrangement of magnets 12, which can have a North (N) and a South (S)pole, to direct magnetic-particle formulations or agents 20 applied awayfrom the targeted site (e.g. on the surface near the targeted site, orin the vicinity of targeted tissues) to the targeted site. Using thisprinciple, the device with its plurality of magnets or magnetic elementscan, for example, direct the agent from the fluid/gel solution to thetarget site.

In one embodiment, agents or active agents, e.g. particles associatedwith a therapeutic agent, can be applied away from a target site (e.g.ear canal or skin) and the device 10 can “push” or apply a force (F) onthe particles to the target site (T). One embodiment includes a methodfor directing agents from the middle ear to the inner ear. Anotherembodiment includes a method for directing agents from the ear canal tothe middle ear. Another embodiment includes a method for directingagents from the ear canal to the middle ear, and further directingagents to the inner ear.

In another embodiment, a method for treating a patient or animalcomprises (a) placing a device proximal to the patient's ear or animal'sear, and (b) magnetically pushing an agent or active agent from the earcanal to the middle ear or from the middle ear to the inner ear. Thismethod can be used to push an active agent from the ear canal to themiddle ear and then to the inner ear. Alternatively, the active agentmay be placed in the middle ear and subsequently pushed to the innerear. Such methods can be atraumatic, can deliver a therapeuticallyeffective amount or a concentrated dose of the agent to the middle orinner ear. In some examples, the method can effectively treat middle andinner ear diseases such as middle ear infections (also known as otitismedia or glue ear), tinnitus, sudden hearing loss, and Meniere's diseaseby local/topical treatment.

FIGS. 2A and 2B illustrate one specific method to deliver active agents20 to the middle ear. As shown in FIG. 2A, the magnetic device 10 iscapable of directing or applying a force F on magnetic or magnetizableagents 20 (e.g. magnetic nanoparticles coated with drugs), which can beused to direct such agents to the middle ear. To reach the inner earwithout first puncturing the ear drum, the agents could be placed in theouter ear and the magnetic device or injector could be used to directthe agents first from the outer ear into the middle ear, and then fromthe middle ear into the inner ear. To do so, the magnetic injector couldbe applied once, or for a longer time period, or it could be appliedmultiple time in two different orientations to provide a path of theagents from outer to middle and then middle to the inner ear. The agentor agents may be placed in the outer ear or ear canal, in a liquid, gel,or via other techniques.

More particularly, FIG. 2B further illustrates the method by showingthat the force F, resulting from the magnetic field, can direct theagent placed in the ear canal to the middle ear. The human ear includesthree primary spaces, the outer ear canal, also known as the externalacoustic meatus, the middle ear and the inner ear. The middle ear isadjacent to the outer ear canal and is separated from the outer earcanal by the tympanic membrane, also known as the ear drum. As can beseen, the magnetic device may then be held near or proximal the ear toapply magnetic forces on the agents. The magnetic forces F then “pushes”or directs the agents 20 through the ear drum (tympanic membrane) andinto the middle ear. In some examples, it is possible to deliver agentsto the middle ear without puncturing the ear drum.

FIG. 3 illustrates a method to deliver active agents from the middle earto the inner ear. In this embodiment, a magnetic device 10 can direct orapply force on magnetic or magnetizable therapeutic agents (e.g.magnetic nanoparticles coated with drugs) to direct such agents to theinner ear. The agents may be placed in the middle ear using conventionalor future developed techniques, e.g., surgical techniques. The force,resulting from the magnetic field, can direct the agents placed in themiddle ear to the inner ear. As can be seen, the magnetic device maythen be held near the ear to apply magnetic forces on the agents. Themagnetic forces F then “push” or direct the agents through the roundwindow membrane and/or oval window membrane and into the inner ear. Insome examples, it is possible to deliver effective amounts of agents tothe inner ear where previously delivery of such agents was not feasible.

As can be seen from FIGS. 2A, 2B, and 3, one specific embodimentincludes a method for delivering a therapeutic agent from the ear canalto the inner ear. More specifically, the active agent may be placed inthe outer ear and then be pushed to the middle ear and then subsequentlyto the inner ear.

Another embodiment includes a device for delivering magnetizable agentsto a treatment site. An arrangement of magnets creates a magnetic fieldthat results in push forces, and these forces can be used to push in(magnetically inject) magnetic or magnetizable agents. Moreparticularly, the device pushes outwards or magnetically injectsmagnetic or magnetizable carriers through tissue or materials.Specifically, it creates forces on magnetic, paramagnetic,ferrimagnetic, ferromagnetic, or superparamagnetic materials, andtransports them outwards from the device (e.g., the magnetic injector).In specific examples, the device can be configured for ear treatments.

One exemplary device suitable with this method includes a device thatincludes a housing and a plurality of magnetic elements or magnets ormagnetization that may be capable of generating magnetic fields.Typically, a single magnet can have field lines around it. The magnetcan be set at an angle that creates a magnetic field along thehorizontal x-axis at a desired location. A second magnet, with anopposite polarity, can be placed and angled in a configuration withrespect to the first magnet so that the magnetic field is equal andopposite (along the minus x-axis) at the same desired location. Thecancellation of the two fields can then create a node—a magnetic fieldzero or minimum. In one example, these two magnets are arranged suchthat the two magnetic fields overlap and can cancel at the location ofthe desired node point without canceling around that point. In oneembodiment, a local magnetic field minimum can be created with a highermagnetic field surrounding the node. This creates magnetic forces, fromregions of low to high magnetic field strength—from the node out—andthus push the magnetic or magnetizable agents away from the magneticinjection device.

Alternatively, an exemplary device suitable with this method includes adevice having a housing and an electromagnet. The electromagnet may becapable of generating magnetic fields, which result in forces that candirect or push a therapeutic agent or other agent.

The plurality of magnetic elements are disposed in the housing and themagnetic field can have the effect to displace the agent from the outerto the middle ear, and can also direct it further into the inner ear, ata rate determined in part by the strength of the magnetic field. Themagnetic device 10 can push therapeutic agents to the middle and/or theinner ear.

In use and practice, active agents, including magnetic or magnetizableagents, can be for example magnetic nanoparticles coated with orcontaining drugs or other therapy, can be delivered from an initiallocation to another site (e.g., a treatment site). For example, suchagents can be placed on the skin or other surface as agents in a fluid(e.g. nanoparticles suspended in water), or agents in a gel, or as apowder, or as a paste, delivered in or via a flow, or by any other meansthat will reliably deliver them to a starting location. Then, the deviceis held in the vicinity of the magnetic or magnetizable agents, in sucha way that the forces generated on the agents push the agents from thestarting to a desired location or treatment site. This magneticinjection force can transport the agents through a barrier. For example,the starting location could be, respectively, the surface of the skin orit could be the outer or middle ear, and then the magnetic force on theagent can be used to transport them, respectively, through the skin,surface of the ear canal, or ear drum or window membranes, into the skinand middle or inner ear, respectively.

The initial placement of the agent or therapeutic agent can beaccomplished in numerous ways. For example, such agents can be placedusing the direct access to the outer ear in a liquid, a gel, by anatomizer (in a spray), or by other techniques. For another example, theagents may be placed in the middle ear using a syringe, scalpel, laserincision, or a tube through the ear drum (tympanic membrane).

The formulations of the pharmaceutical compounds or active agents thatcan be administered in connection with the methods comprise therapeuticagents, pharmaceutical agents (such as steroids, anti-inflammatory, oroto-protectant agents), molecular agents, nucleotides, or proteins.

The agents or magnetic agents or therapeutic agents can be or caninclude therapeutics, drugs, proteins, or gene therapy, either by havingthese materials themselves be magnetic (e.g. a drug molecule that ismagnetic or magnetizable), by incorporating magnetic materials either ona molecular basis (e.g. drug molecules that include iron) or by beingbound or attached to magnetic materials. Magnetic agents that are madeby placing magnetic materials inside or attaching them to non-magneticobjects (e.g. to starch or polymer objects, to/in micelles, liposomes,viruses, bacteria, cells) can themselves be therapeutic or can furthercontain therapeutics, drugs, proteins, or gene therapy on their surfacesor inside them. Non-magnetic agents (such as therapeutics, drugs,proteins, or gene therapy) can also be magnetically pushed by attachingthem to or containing them inside agents that are or have been mademagnetic. Binding, encapsulation, coatings, and other means may bechosen to select the therapy release rates (slow or fast), release times(immediately or after a certain duration), and conditions under whichrelease will occur (pH, osmolarity, or other parameters) to mostefficaciously treat target regions or locations. The agents may beformulated into powders, suspensions, gels, sprays, lotions, or otherformulations known in drug delivery.

Therapeutics and drugs can include steroids (e.g. dexamethasone,prednisone, methylprednisolone, betamethasone), prostoglandins,anti-inflammatory agents, aminoglycosides, antibiotics (e.g. glycosides)or other drugs, and nucleotide or gene therapy. They can includetarget-specific ligands, linkers to other moieties, polar or non-polarmoieties, and elements that can be used to help transport agents acrossphysiological barriers.

Such pharmaceutical compositions can contain a therapeutically effectiveamount of active ingredients, and, as may be necessary, inorganic ororganic, solid or liquid pharmaceutically acceptable carriers.Pharmaceutical compositions suited for topical/local administration tothe inner ear include aqueous solutions or suspensions, which may eitherbe ready to use or require preparation prior to use (e.g.lyophilisates). Suited pharmaceutical compositions further include gels,which may be biodegradable or non-biodegradable, aqueous or non-aqueous,or micro- or nano-sphere based. Examples of such a gel include, but arenot limited to, carbomers, poloxamers, alginates, hyaluronates,xyloglucans, polyesters, polysaccharides, poly(lactides),poly(glycolide) or their co-polymers PLGA, sucrose acetate isobutyrate,and glycerol monooleate, whereas the gel may be formed in situ or priorto use from solutions or suspensions. These compounds further includecreams and ointments, emulsions, micro-emulsions or self-emulsifyingcompositions. Pharmaceutical compositions suited for enteral orparenteral administration include tablets or gelatin capsules or aqueoussolutions or suspensions as described above.

The agents, including pharmaceutical compositions, may be sterilizedand/or may contain adjuvants, e.g. preservatives, stabilizers, wettingagents and/or emulsifiers, salts for regulating the osmotic pressureand/or buffers, penetration enhancers, bio-adhesive agents. Thepharmaceutical compositions of the invention may, if desired, containfurther pharmacologically active substances, such as, but not limited toantibiotics or analgesics. They may be prepared by any of the methods,e.g. by conventional mixing, granulating, confectioning, dissolving orlyophilizing methods, and contain from about 0.01 to 100% of activeingredient.

The amount to be administered may vary, depending upon the method ofadministration, duration of therapy, the condition of the subject to betreated, and the severity of the ear disease. In one example, theduration of therapy may range between one minute (or less) and severalhours for a single treatment, and could be administered once or multipletimes over a period of days, weeks, months, or years, and may extend upto chronic treatment. The therapeutically effective amount of thecompound to be delivered may range between pico-grams to milligrams.

The agent should be magnetic or magnetizable (that is associated withmagnetic materials). Magnetic materials suitable for site-directeddelivery can be incorporated in the coating of an oral dosageformulation or inside the oral dosage formulation and used forsite-directed delivery. Alternatively, the agent can be appliedtopically and then delivered to the targeted site. Further, the agentcan be delivered intravenously and then delivered to the targeted site.

Magnetic materials can include paramagnetic, ferrimagnetic,ferromagnetic and superparamagnetic materials (e.g. iron containingcompounds), martensitic stainless steels (e.g. 400 series), iron oxides(Fe₂O₃, Fe₃O₄), neodymium iron boron, alnico (AlNiCo), and samariumcobalt (SmCo₅). Moreover, individual magnetic materials have been shownto possess properties that can be combined to achieve localizeddelivery. Ferromagnetic and superparamagnetic compounds include but arenot limited to iron-containing compounds such as martensitic stainlesssteels (e.g. 400 series), iron and iron oxides (Fe₂O₃,Fe₃O₄).

If the agent is diamagnetic or if the magnetic material associated withthe agent is diamagnetic, then the combined force from the device orsystem can attract the agent or associated diamagnetic material.Diamagnetic materials, all paired electrons, are slightly repelled by amagnetic field. Diamagnetic properties arise from the realignment of theelectron orbits under the influence of an external magnetic field. Theuse of diamagnetic materials may reverse the interactions with thedevice or system.

In one exemplary embodiment, the magnetic material is in the form ofmicron-sized or sub-micron-sized particles. Such particles may beincorporated in micro or nano-carriers, optionally the micro ornano-carriers contain an active agent to be delivered. Suitable sizesfor the magnetic material range from nanometers up to centimeters incross-sectional diameter or width. In another exemplary embodiment, themagnetic material is larger than 10 nanometers in length, width, and/ordiameter, and may have any shape (e.g. tubes, ellipses, etc.).

Magnetic particles may be incorporated into cells or attached to cellsurfaces. In certain exemplary embodiments, magnetic particles may befed to the target cells or temporary pores may be created in the cellmembrane of the target cell by electroporation. In other exemplaryembodiments, magnetic particles may be attached to the cell surface viaan antibody binding to cell membrane receptors or through chemicalconjugation of the magnetic particle to the cell membrane.

One or more agents may be formulated alone or with excipients orencapsulated on, in or incorporated into the microparticles ornanoparticles. Suitable agents include therapeutic, prophylactic, anddiagnostic agents. These agents include organic or inorganic compounds,amino acids and proteins, sugars and polysaccharides, nucleic acids orother materials that can be incorporated using standard techniques.

In some exemplary embodiments, the magnetic fields may be provided inthe form of one or more materials that are magnetic, i.e., that eitherexhibit a permanent magnetic field or that are capable of exhibiting atemporary magnetic field. The entire device, or selected portionsthereof, may be manufactured from the one or more magnetic materials toprovide a magnetic field generator. For example, a predeterminedquantity of magnetite or an alloy thereof may be included in theconstruction of the device. Other materials may be utilized in additionto or in place of magnetite to provide the desired magnetic properties.Such materials may be temporary magnetic materials or permanent magneticmaterials. Some examples of suitable magnetic materials include, e.g.,magnetic ferrite or “ferrite”, which is a substance consisting of mixedoxides of iron and one or more other metals, e.g., nanocrystallinecobalt ferrite. However, other ferrite materials may be used. Anotherexample of a magnetic material is Neodymium, Cobalt, or other alloys ofrare-earth elements.

In some exemplary embodiments, the agents may be biocompatible. Suchagents may further be eliminated by natural processes from the middleand inner ear after treatment (e.g. via the Eustachian tube, via thelymphatic system, by metabolism, by mucosal uptake and delivery to theblood, and by other physiological means) and may eventually be clearedfrom the inner or middle ear. Nevertheless, if after the magneticallyinjected therapy has acted in the middle or inner ear (for example,after drugs have been released from the agents into the middle or innerear), if it is desirable to remove the agents from the middle or innerear, a magnet could be held near that ear. In reverse to the magneticinjection device, which applied injection forces, this magnet would pullthe agents back out.

The term “therapeutically effective” refers to an amount of compositionthat is sufficient to ameliorate one or more causes or symptoms of adisease or disorder. Such amelioration only requires a reduction oralteration, not necessarily elimination of the disease or disorder. Atherapeutically effective dose includes an amount effective to produce adesired effect, such as reducing or eliminating middle ear inflammation,reducing tinnitus (the perception of sound when none is present), orfully or partially restoring hearing.

Agents made from or contain magnetic, paramagnetic, ferrimagnetic,ferromagnetic, or super-paramagnetic materials. They can be of any shapeor size, although spherical, elliptical, or rod shape agents are common,and they can have a variety of coatings. These agents will contain or beattached to therapeutics, or will themselves be therapeutic.

The sizes, shapes, and coatings of agents can be varied and selectedbased on application parameters. The magnetic force on an agenttypically varies with the volume of magnetic or magnetizable materialsin that agent. Thus, to increase magnetic forces, it is desirable tochoose larger agents. However, larger agents may experience largerbarrier resistance to motion—for the same magnetic force, it may be moredifficult to move a larger agent through a biological barrier such as atissue membrane like the ear drum or window membranes. Larger agents mayalso create more damage to tissue as they move through it. For thisreason, there can be a tradeoff: it may be suitable to pick agents thatare big enough to experience sufficient magnetic forces but small enoughto move through tissue barriers easily and without causing undesirabledamage. Agents may be selected to have coatings or surfaces that alloweasier passage through tissue barriers.

The magnetic forces created on agents by applied magnetic fields areknown to a degree. For example, it is known that the magnetic forcetypically scales with the volume of magnetic or magnetizable material inthe agent. Forces on agents can also be measured. Thus agents can beselected to provide a desired degree of magnetic forces.

Tissue forces on agents, the forces that resist motion through tissuebarriers, may be accessed. Thus we disclose carrying out tissue andanimal experiments to measure tissue/barrier resistance to agent motionas a function of agent size, shape, and coating. A sample experiment isto take agents of various sizes and measure their motion through atissue sample of specified thickness under a carefully applied magneticfield for a variety of agent shapes, sizes, and coatings. The data fromsuch measurements can be used to determine tissue resistance to agentmotion for various agent sizes, shapes, and coatings. A measurement ofthe motion of the agent through tissue may be used to assist inoptimization. In contrast, magnetic forces on agents can be accuratelypredicted in many cases, but if/when they cannot, then experiments canbe used instead.)

Once magnetic forces and tissue/barrier resistance have been determined,either by calculations and/or via experimental measurements, thenoptimal agent size, shape, and coatings are chosen to provide theoptimal tradeoff between magnetic forces and tissue/barrier resistance.In one example, for directing spherical ferromagnetic nanoparticles intothe inner ear over adult human distance (3-5 cm from magnetic injectiondevice to agents placed in the middle ear), an effective sample size ofnano-particles with iron cores is approximately 350 nm in diameter. Inother example, magnetically injected particles as small as 20 nm and aslarge as 1 micrometer may be pushed by the device.

Methods and devices disclosed herein may be used with animals andhumans. The term “subject,” and “patient” are used interchangeably torefer to any individual who is the target of administration ortreatment. The subject can be a vertebrate, for example, a mammal. Thus,the subject can be a human or veterinary patient.

EXAMPLES

The disclosure will be further described in connection with thefollowing examples, which are set forth for purposes of illustrationonly.

Exemplary 1 Magnetically Directing Therapeutic Agents into the Inner Ear

The magnetic device can be used to deliver therapeutic magnetic ormagnetizable agents to the inner ears of animals and humans. Themagnetic or magnetizable agents were placed in the middle ear by asyringe through the ear drum. The magnetic device can then held so thatmagnetic forces on the agents act to transport them from the middle earinto the inner ear.

Example 2 Magnetic Device

Shown in FIGS. 1 and 2A is a magnetic injection device and a method toapply it to direct magnetic or magnetizable agents through the ear druminto the middle ear. In this example, the device consists of two or moremagnetic elements that are arranged to create a magnetic field strengthminimum—forces on magnetic or magnetizable agents emanate outwards fromthis minimum and create the pushing forces.

Example 3 Device with Two Domains

FIG. 4 shows a schematic diagram of a device of single magnet with atleast two domains (two sub-magnets) magnetized in two differentdirections. This magnet was optimized to magnetically inject agents intothe inner ear at adult human face-to-inner-ear distances (3-5 cm).

The orientation of the magnetization was selected to create a maximumforce at a desired location. The device in rat experiments was able toinject magnetizable nano-particles into rat inner ears. Themagnetization direction is the direction from “South” to “North” withineach magnet or sub-magnet, and can be chosen and built to point in anydesired direction. It was not necessary that North and South alwayscorrespond to the ends of a rectangular magnet, the South-to-Northdirection can be at an angle within the bar magnet. Suitable locationswould correspond to the middle or inner ear in animal or human patients.To create maximal strength magnetic injection forces at a desiredlocation, the magnetization directions of the elements are chosen tocreate the most effective magnetic field strength minimum and to placeit at a desired location.

This example made it evident that other devices could have as few as twoelements (two sub-magnets), or it could have a larger number ofelements.

Example Device

As shown schematically in FIG. 5, one exemplary device 10 can make useof magnetic elements or magnets that may be capable of generatingmagnetic fields. In this example, these two magnets are arranged suchthat the two magnetic fields overlap and can cancel at the location ofthe desired node point without canceling around that point. The devicehas two magnetic elements 12 in which the first magnetic element and thesecond magnetic element each produce a magnetic field. The magneticfields are represented by magnetic flux lines that extend from twomagnetic poles. The plurality of magnets 12 can be placed at an angle toone another and the magnetic field lines are able to cancel out, orotherwise combine together in a fashion that creates a lower magneticfield strength, so as to form a local magnetic field minimum outside thecentral space 30. More particularly, the first magnetic element and thesecond magnetic element define a central space between the first and thesecond magnet.

The central space is the volume defined by the arrangement of theplurality of magnets and is the physical space between the magnets. Thecentral space or region is defined by the physical space between themagnets that can be the least volume enclosed by a minimal convex shape,wherein the convex shape includes all material points of all themagnets. More particularly, this shape or space can be defined by commonmathematical usage in that if any two points are in the volume of thespace or region then the line between them is wholly included in thevolume of the shape or region. A convex shape is minimal if it is thesmallest convex shape that can contain all the material points of allthe magnets. The central space is at least the remaining volume in sucha minimal convex shape.

The first magnetic field and the second magnetic field overlap to createa combined magnetic field and create a local magnetic field strengthminimum outside the central space. The combined magnetic field in frontof the local minimum can produce a force on the agent. The magneticfield strength can be between 1 micro-Tesla and 8 Tesla.

Example 5 Animal Experiments

Animal experiments were conducted to test and validated device describedin Example 3. The device was made by bonding two magnets together, witheach magnet magnetized as shown by the “S→N” (South to North) markings.It was tested on rats, but it was held at a human adult 4 cm distancefrom device to inner ear distance. The device was composed of a singleblock of material.

1. A method for treating a patient comprising: (a) providing a deliverydevice capable of generating a magnetic field; (b) placing the deviceproximal to a patient's ear; and (c) pushing the agent into thepatient's ear via the device, wherein the therapeutic agent is pushed toa treatment site.
 2. The method as claimed in claim 1, wherein the agentis magnetic, superparamagnetic, ferrimagnetic, ferromagnetic, orparamagnetic.
 3. The method as claimed in claim 1, wherein the agent iscombined with a material that is magnetic, superparamagnetic,ferrimagnetic, ferromagnetic, or paramagnetic.
 4. The method as claimedin claim 1, further comprising the step of pulling the agents.
 5. Themethod as claimed in claim 1, wherein an effective amount thetherapeutic agent is pushed into the patient's middle ear by themagnetic field.
 6. The method as claimed in claim 1, wherein aneffective amount of the therapeutic agent is pushed into the patient'sinner ear by the magnetic field.
 7. The method as claimed in claim 1,wherein the therapeutic agent is biodegradable.
 8. The method as claimedin claim 1, wherein the device comprises a plurality of magneticelements in which at least two magnetic elements are arranged at anangle.
 9. The method as claimed in claim 1, further comprising the stepof placing the agent within the middle ear of the patient.
 10. Themethod as claimed in claim 9, further comprising the step of pushing theagent from the middle ear to the inner ear.
 11. A method to decreaseinner ear or middle ear trauma in a subject while treating the subjectcomprising (a) placing a device, capable of generating a magnetic field,proximal to a patient's ear; and (b) pushing agents into the patient'sear via the device, wherein the tympanic membrane is not materiallypunctured during the treatment.
 12. The method as claimed in claim 11,wherein the device comprises a plurality of magnetic elements in whichat least two magnetic elements are arranged at an angle.
 13. The methodas claimed in claim 11, wherein the device comprises a plurality ofmagnetic elements having magnetization at an angle.
 14. The method asclaimed in claim 11, further comprising the step of placing the agent inthe ear canal of the subject.
 15. The method as claimed in claim 11,further comprising the step of placing the agent within the middle earof the patient.
 16. A device configured to push agents into a subject'sear comprising a plurality of magnetic elements wherein the devicecomprises a plurality of magnetic elements in which at least twomagnetic elements are arranged at an angle.